The endogenous cannabinoid system is a neuromodulatory system that affects a wide range of physiological processes, including memory and inflammation. Evidence indicates that exogenous and endogenous cannabinoids are neuroprotective and thus there is interest in the therapeutic potential of cannabinoids in Alzheimer's disease. In vitro studies have shown that cannabinoid receptor activation can inhibit or reduce the deposition of beta-amyloid plagues and decrease inflammation, critical features of Alzheimer's disease. Moreover activation of the cannabinoid system has neuroprotective effects. While these findings indicate that cannabinoids may be beneficial in attenuating the neuropathology associated with Alzheimer's disease, very few studies have evaluated if stimulation of the endocannabinoid system can attenuate cognitive deficits and neuropatholgy in in vivo models of Alzheimer's disease. The goal of these studies will be to examine whether elevating endogenous levels of the endocannabinoid anandamide via inhibition of its primary degradative enzyme fatty acid amide hydrolase (FAAH), will have beneficial effects on memory impairments and neuropathological markers in 3xTg mice, an in vivo model of Alzheimer's disease. More specifically, we will determine whether repeated administration of the FAAH inhibitor PF-3845 improves learning and memory and prevents or delays neuropathological processes of Alzheimer's disease. The findings from these proofs of principle studies may lead to the identification of a new therapeutic agent for memory deficits and neuropathology associated with Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Current treatments for Alzheimer's disease provide some symptom relief, but do not reverse or slow neuropathology in Alzheimer's disease. The proposed studies will evaluate whether a drug that elevates the endogenous cannabinoid ligand anandamide will have beneficial effects on cognitive decline and neuropathogenesis in a mouse model of Alzheimer's disease. Results from these studies may lead to a novel treatment for Alzheimer's disease.